Transcript:Adam M. Brufsky, MD: So then we go. So now we’ve agreed, kind of, fulvestrant, and I agree. I mean I think that it’s 500 mg, we don’t even know whether it’s oral. And now we’re on to the CDK4/6 era where we’re not using single-agent aromatase inhibitors (AIs) anyway. But now the question is, so now we’re using fulvestrant, right? Do we combine it with palbociclib? That’s the next thing. So now we’ve got PALOMA-2, Hope, which is combining palbociclib and letrozole.

Hope S. Rugo, MD: So you know, the whole world of hormone receptor-positive disease now, in the metastatic setting, is about targeted therapy and how we can improve response. And we talk about reverse resistance, but really what we’re trying to do is improve response to endocrine therapy and improve the duration of response. I think those are our two biggest goals. And the CDK data is really fascinating because it came from UCLA. Dennis Slamon, was as usual looking ahead to the next step and where things can come from. They have a series of cell lines at UCLA and they were able to expand this research further and show that where CDK inhibitors were most likely to have a benefit was in estrogen receptor (ER)-positive—like disease, and HER2-positive disease, which is another area.

Adam M. Brufsky, MD: Which is totally counterintuitive.

Hope S. Rugo, MD: Yeah, it was. And I remember somebody telling me from one of the companies that has a CDK inhibitor, “Well it’s only luminal B’s,” but we don’t know that. There are absolutely no data that show it. But there will be data coming out of these trials, I think, that tells us more about it.

Adam M. Brufsky, MD: Right.

Hope S. Rugo, MD: But I think that the idea is HER2, whereas for example in the triple-negative or mesenchymal-like cell lines, had no activity at all. So those were very intriguing data and led to the phase I and then the phase II trial, PALOMA-1, which of course, I think, somewhat surprisingly for many of us led to accelerated approval in the first-line setting with letrozole. So the FDA approval. The phase III trial had already completed accrual, which is one of the requirements of the FDA. So PALOMA-2 is this me-too-like trial. So letrozole you didn’t relapse within a year on an AI, but you could have received hormone therapy before, letrozole/placebo versus letrozole/palbociclib. And these trials are really interesting because they’re all weighted towards the novel agents.

So we’re going to have a lot of data with the novel agent. It means they do a little bigger trial or they expect a huge benefit, which is a downside in analyzing results statistically. But that was a 3 to 1 trial. So then for PALOMA-3, of course, the next step is, well what happens in those people who relapsed on an AI and are going to go on fulvestrant? So the PALOMA-3 trial was palbociclib and fulvestrant versus fulvestrant and placebo, a 2:1 randomization. What’s fascinating about this trial is that it started long after PALOMA-2, but it reported at least a year in advance we expect about a year in advance, right? And that’s because, of course, the time-to-progression is so much shorter in the second-line setting.

But PALOMA-3 showed a doubling of time-to-progression or progression-free survival when you added palbociclib to fulvestrant. And interestingly, although a third of the patients had received one line of prior chemotherapy, there was no real difference in toxicity. And, in fact, comparing it to PALOMA-1, many fewer patients stopped drug due to toxicity. We all got kind of used to the neutropenia in managing the drug. So it’s actually I think a fascinating dataset. No survival data yet.

Adam M. Brufsky, MD: They didn’t present the survival data?

Hope S. Rugo, MD: There were not enough events. I mean nobody’s dead yet. So I mean thankfully there’s like a handful of people.

Adam M. Brufsky, MD: What did they present at the San Antonio Breast Cancer Symposium then?

Joyce A. O’Shaughnessy, MD: Subset analysis.

Adam M. Brufsky, MD: Was it subset analysis? I thought they presented the survival.

Hope S. Rugo, MD: Just updated analyses. But the interesting thing I think also is that if you think about it, people said well, you know, palbociclib in the first-line setting, you don’t have to give it, there’s no survival advantage. But we go back, we all used AIs, right, first-line, in a patient who’s not on hormone therapy. And that’s based on trials, none of which that showed a survival advantage. So I think that the issue is, it’s very hard for us to power these trials for survival advantages and it’s going to be hard to know. So we’re going to see results from PALOMA-2 sometime in 2016. We’re going to see results from the two other very interesting studies. So there’s the MONALEESA Trial with ribociclib, Novartis’ CDK4/6 inhibitor. And then there’s a third CDK4/6 inhibitor which is a little bit different from the others, abemaciclib, from Lilly, and that drug had single-agent activity, which the other two don’t seem to have much of. And it was really fairly impressive single-agent activity in phase I. So they did a single-agent phase II trial, a MONARCH Trial, and that trial will also be presented either at AACR or ASCO is my guess. I mean all this is event-driven. But that’s single-agent drug in refractory hormone receptor positive. And then, of course, they also have their fulvestrant study.

Adam M. Brufsky, MD: Was that a phase II or a phase III?

Hope S. Rugo, MD: Phase II.

Sara A. Hurvitz, MD: And it’s continuous dosing, which is also interesting because of the relative lack of cytopenias seen with abemaciclib, but more of the liver and gastrointestinal.

Hope S. Rugo, MD: Everybody who takes abemaciclib gets diarrhea, but it’s not neratinib-like diarrhea, and so you don’t have to take upfront prophylaxis but you have to be taking Imodium. So my patients who are on abemaciclib for a long time traveled with the Imodium.

Sara A. Hurvitz, MD: One of the things I loved about PALOMA-3 was that they allowed premenopausal women to be enrolled.

Hope S. Rugo, MD: I agree.

Sara A. Hurvitz, MD: Fifteen or 18 percent or so and showed benefit in the Forest plot.

Hope S. Rugo, MD: That I think was such a silly thing that the studies have said you had to be postmenopausal either by age or have your ovaries out, that you couldn’t get an injection. And this trial I think really made a big difference in changing that.

Adam M. Brufsky, MD: That’ll change, I think, the way we do trials in the future.

Sara A. Hurvitz, MD: Although you have to be aware that 20% or so of patients will have ovarian function breakthrough. So while I don’t care so much about that on fulvestrant, with the aromatase inhibitors it may be to their detriment. So especially in the curative setting where a lot of us, not to get back to the early breast cancer setting, but I think it’s an important point to make clinically that periodically monitoring estradiol level is probably important when we begin an AI.

Hope S. Rugo, MD: You know it’s interesting that you say that because we’re finishing up the ASCO Guidelines for hormone therapy for metastatic hormone receptor positive breast cancer…

Adam M. Brufsky, MD: Put in the measure— are you going to put it in?

Hope S. Rugo, MD: Well I’ve put it in. It’s been taken out, three times.

Sara A. Hurvitz, MD: That’s why you were giggling in the corner?

Adam M. Brufsky, MD: Well now say put it back in. ASCO, we’re saying put it back in.

Hope S. Rugo, MD: Well I have to be very diffuse about the comment because in truth all of the people who were involved in these guidelines have said there are no data to support that.

Sara A. Hurvitz, MD: SOFT study.

Adam M. Brufsky, MD: There was a lot of data to support that.

Hope S. Rugo, MD: No, there is no data to say that you’re going to do worse if your estradiol is 20 or 30 or 40.

Adam M. Brufsky, MD: Oh, I see your point.

Hope S. Rugo, MD: Or 30 or 40 or 60, we just don’t know. We just believe it.

Adam M. Brufsky, MD: But there are data that suggest that, as Sara said, you know 15, 20% of women will not have suppressed estradiol.

Hope S. Rugo, MD: The question is, do they do worse and do you have to monitor. And I monitor and I feel strongly about it also, but we don’t know actually.

Adam M. Brufsky, MD: Are we ever going to know that?

Hope S. Rugo, MD: No.

Adam M. Brufsky, MD: That’s the problem.

Christy A. Russell, MD: Well, the other thing is that people get very casual about starting to go with every 3 months or every 4 months, injections.

Hope S. Rugo, MD: Yup.

Adam M. Brufsky, MD: Right, that’s a whole other issue.

Christy A. Russell, MD: And it just frightens me to watch that happen thinking that they’re getting any suppression. There’s no escape that’s going to happen.

Joyce A. O’Shaughnessy, MD: I just wanted to make the point about the PALOMA-3 data from San Antonio, the subset analyses looking at the fulvestrant with the palbociclib. I was surprised because it looked as though no prior endocrine therapy (was given) except for relapsing in the adjuvant setting; one prior endocrine; and then even two prior endocrines—very nice delta with the palbociclib. It was like 1.8 months of fulvestrant alone, which is obviously poor, and way up there, you know, a much, much higher range, like in a 9-month range, with the fulvestrant and palbociclib. So even in patients who have had several lines of therapy, there was still nice benefit there. So that was helpful to see.

Hope S. Rugo, MD: Yeah there were small subsets in that group. But I also agree. I thought that was nice to show.

Christy A. Russell, MD: But this is a beauty of riches now and the sequencing of these therapies.

Adam M. Brufsky, MD: Well, here we go. So let’s talk; because that’s the first thing. So we all think it’s great, PALOMA-3. But now we have the buparlisib, we have the BELLE-3 Trial; they first got it in BELLE-2 actually. Joyce, can you comment on BELLE-2 and let us know about it?

Joyce A. O’Shaughnessy, MD: Yes. So that was also a fulvestrant backbone. It was in patients who had progressed on a nonsteroidal AI. Fulvestrant/placebo versus the pan-PI3 kinase inhibitor buparlisib, oral agent, with fulvestrant. It was technically a positive trial. It met its primary endpoint of progression-free survival with about a two-month improvement. However, the consensus is that it really wasn’t clinically meaningful because the toxicity of buparlisib, quite a lot, some liver toxicity, hyperglycemia, mood disorders, etcetera. So it really wasn’t clinically meaningful.

They looked at the paraffin blocks, which of course were mostly primary archival tissue going back some years. They looked for PI3 kinase pathway activation, PIK3CA mutations, pTEN loss—not useful in terms of predicting outcome, even though it was stratified based on that—not useful. They got a baseline blood draw for circulating tumor DNA, looked for that PIK3CA mutation, so not the pTEN story, but just the PIK3CA very helpful in terms of delineating patients. Big benefit from the buparlisib. Quite interesting, very helpful to see. I think we might have a new way to enrich these patients, which is very exciting.

Adam M. Brufsky, MD: Which I think is great. That, to me, is the first real proof. That, to me, was the biggest thing out of the whole paper, was that it was a real proof of concept.

Joyce A. O’Shaughnessy, MD: Exactly.

Adam M. Brufsky, MD: Of circulating DNA.

Hope S. Rugo, MD: But what about the numbers? To me, it was such a tiny subset. I thought that it’s hypothesis-generating, but it can’t change what we do because you have to have a study where 85% of your patients have data and not 10% or whatever it was, 15 or 20%, not even. And the numbers weren’t balanced between the two arms well. So it’s fascinating. But you can’t run forward with it, but maybe what you can do is incorporate it into other trials. It can’t save this agent probably.

Adam M. Brufsky, MD: I mean, buparlisib as an agent with fulvestrant probably is not going to be taken to the next level.

Joyce A. O’Shaughnessy, MD: No, not going to be going forward.

Adam M. Brufsky, MD: The pan-PI3 kinase inhibitors, I mean they’re going to have to be more targeted, alpha-specific or whatever, and that’s where people are going with this.

Joyce A. O’Shaughnessy, MD: It seems that that’s the way things are evolving, yes.

Adam M. Brufsky, MD: But I’m not sure even those. I mean, I’m kind of concerned about the toxicity.

Hope S. Rugo, MD: I love the alpha-specific.

Adam M. Brufsky, MD: Do you really?

Hope S. Rugo, MD: Now, I haven’t used taselisib which I understand has some differential toxicities like colitis which I haven’t seen with alpelisib, but alpelisib (BYL-719) and that’s an alpha-specific PI3 kinase inhibitor. I have a patient on it who she had everolimus for 18 months and was good, developed liver metastases, waited to get on this phase I trial of fulvestrant and alpelisib. We’re all biting our fingernails. And she went on it two-and-a-half years ago and she has no liver mets left. So she’s had essentially a visceral CR.

Adam M. Brufsky, MD: Did she have a PI3 kinase mutation, circulating DNA mutation?

Hope S. Rugo, MD: So they sent out something with some updates saying the only patients who responded had PI3 kinase mutations, and I e-mailed back and said, well, what about my patient? They said, well, she had archival tumor tissue. The bottom line is that we kept biopsying her liver. We couldn’t get enough tumor tissue, so we used her old tumor and that tumor did not have a PI3 kinase mutation.

Adam M. Brufsky, MD: What about her blood? Did you do a blood test?

Hope S. Rugo, MD: We could at some point. She’s still responding, so at some point we could look and that would be useful information. But she’s not the only one. I have two patients who are on that phase I trial who are still on it 2+ years. So I think that, and it seems to be, other than this long-term hyperglycemia, so even if you don’t get hyperglycemia early, you can get it late. But if you don’t get a rash right away, you don’t get a rash. And rash seems to have nothing to do with the response.

Sara A. Hurvitz, MD: What I like about the circulating tumor DNA that more and more studies are incorporating is it helps overcome this temporal and spatial heterogeneity of tumors.

Adam M. Brufsky, MD: Right, very much so.

Sara A. Hurvitz, MD: This problem with the differences between archived samples and what’s going on now.

Hope S. Rugo, MD: This is great. Great comments, yes.

Adam M. Brufsky, MD: Well, and the fact that in this trial of predicted response, all the criticisms of circulating DNA, well, maybe it’s only a subset of cells that shed tumor, a subset of mets that shed the tumor into the blood. I think that if you can actually use it, if it’s a useful as a predictive marker now for response, I think that’s really cool.

Christy A. Russell, MD: And future trials in the metastatic setting should not be allowing archival tumor tissue to enter into the trial. It needs to completely disappear.

Adam M. Brufsky, MD: It’s either going to be a biopsy of the metastasis or circulating tumor DNA, I’m guessing.

Hope S. Rugo, MD: Because then you can’t biopsy bone so it’s a big issue.

Transcript Edited for Clarity